Different physical methods have been explored to improve the transdermal delivery efficiency of many drugs. Iontophoresis is one of the significant acceptable physical methods for enhancing the penetration of ionic drugs through/into the skin by the application of electric current. Iontophoretic delivery of drugs is dependent on the physicochemical characteristics of the drug and the magnitude of the applied electric field. Due to its noninvasiveness, avoidance of systemic first-pass metabolism, controlling the rate of drug input over a prolonged period of time, and minimization of systemic side effects, iontophoretic drug delivery mechanism has gained significant acceptance in clinical use. In recent years, iontophoretic drug delivery of different drugs has been extensively explored in dermatology, ophthalmology, dentistry, and physical medicine. In the current chapter, historical background, principles and mechanisms, factors, advantages and disadvantages, and applications of iontophoresis in transdermal drug delivery have been comprehensively reviewed. © 2019 Elsevier Ltd. All rights reserved.